The overall goal of this application is to develop enabling technologies for the construction of a very large axial field of view PET scanner with effective performance 100-fold greater than existing systems. Specific Aims: We will (1) use simulations to specify spatial resolution and time of flight capabilities that will achieve 100-fol increase in the square of the pre-whitening signal to noise ratio; (2) Build a dialog with clinical researchers to specify requirements and trade-offs for a useful complete device; (3) Design, fabricate and characterize detectors that meet the performance specified in Aim 1; (4) Develop new factorized, parallelized reconstruction methods that can handle the datasets from the scanner in an efficient and scalable manner; (5) Create accurate simulations of electronics systems capable of supporting the ultra-sensitive PET scanner and model the final design options (6) complete planning and costing for the fabrication of the complete device. Methods: Monte-Carlo simulations will be used to specify scanner requirements. Detectors based on 2 variants of existing scintillator-based approaches will be fabricated and tested. A workshop will be held at which clinical researchers and investigators can discuss design issues relating to the project will be held. Electronics configurations based on the open source OpenPET suite and on designs provided by Toshiba Medical will be accurately simulated in software and their performance in conjunction with the detectors built in Aim 2 tested. The investigators will then finalize a design for the scanner, cost it out and apply for funds to complete the project. In the long term, the scanner will be housed in a National Ultra-sensitive PET Facility and access given to academic and industrial researchers from across the country. Health-relatedness: This application will lay the ground-work for the fabrication of an ultra-high sensitivity PET scanner, which can be used to detect much smaller lesions than is currently possible. In addition it can be used to perform kinetic modeling of physiological parameters across the entire body, which can be used to better characterize pathological conditions. It can be used to perform low-dose longitudinal PET studies. It can also be used to determine drug kinetics and targeting early in the drug development pipeline.